Project Abstract : We have been at the forefront of establishing a new paradigm in cancer biology, by demonstrating that a critical function of key oncogenes, such as Myc and mTOR, in augmenting ribosome biogenesis and protein synthesis rates is essential for tumorigenesis. In the previous funding cycle, we employed a multifaceted approach to show that a specific downstream translation arm of mTOR, 4EB1-eIF4E, is responsible for rewiring the prostate cancer (PCa) proteome and selectively controlling the translation of mRNAs that are critical for cancer cell growth, metabolism, and metastasis. Strikingly, we have also identified a new RNA element in the 5'UTR of these mRNAs, which we have termed the pyrimidine-rich translation element (PRTE) that demarcates and is functionally important for the selective actions of mTOR signaling on translational control. Furthermore, we have also discovered that the most aggressive form of PCa, established by loss of PTEN and MYC hyperactivation, induces profound ?super-augmented? protein synthesis that must be carefully controlled by the activation of appropriate checkpoints to promote cancer cell survival. Strikingly, we find that activation of eIF2? is a specific means to rebalance protein homeostasis as an adaptive response to sustain PCa cell survival. Our genetic and pharmacological preliminary data show that phosphorylation of eIF2?, which reprograms translational control, represents a new point of vulnerability for primary and metastatic PCa cells. Together, these findings lay the foundation for this proposal. In Aim 1 we will define the molecular mechanisms by which trans-acting proteins recognize and specifically bind the PRTE to mediate translational specificity downstream of mTOR in PCa. In Aim 2 we will unravel the precise benefit of blocking P-eIF2? activity and other UPR arms in mice and human PCa, which will pave the way for new therapeutic approaches and the identification of novel therapeutic targets to reign in this currently incurable cancer. In Aim 3 we will also characterize for the first time the subcellular localized translational landscape directed by eIF2? phosphorylation to reprogram the prostate proteome essential in maintaining cellular fitness in PCa cells. Collectively, these studies will offer a new understanding of the post-transcriptional circuitry and synthetic lethal networks that remodel that PCa proteome and can be exploited as new therapies.